Manual Enzymes of Lipid Metabolism II

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Once in the circulation, they can either go to the liver or be stored in fat cells adipocytes that comprise adipose fat tissue found throughout the body. To obtain energy from fat, triglycerides must first be broken down by hydrolysis into their two principal components, fatty acids and glycerol. This process, called lipolysis , takes place in the cytoplasm.

The glycerol that is released from triglycerides after lipolysis directly enters the glycolysis pathway as DHAP. Because one triglyceride molecule yields three fatty acid molecules with as much as 16 or more carbons in each one, fat molecules yield more energy than carbohydrates and are an important source of energy for the human body.

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Triglycerides yield more than twice the energy per unit mass when compared to carbohydrates and proteins. Therefore, when glucose levels are low, triglycerides can be converted into acetyl CoA molecules and used to generate ATP through aerobic respiration. This fatty acyl CoA combines with carnitine to create a fatty acyl carnitine molecule, which helps to transport the fatty acid across the mitochondrial membrane. Once inside the mitochondrial matrix, the fatty acyl carnitine molecule is converted back into fatty acyl CoA and then into acetyl CoA.

Figure 3. Click for a larger image. During fatty acid oxidation, triglycerides can be broken down into acetyl CoA molecules and used for energy when glucose levels are low. If excessive acetyl CoA is created from the oxidation of fatty acids and the Krebs cycle is overloaded and cannot handle it, the acetyl CoA is diverted to create ketone bodies. These ketone bodies can serve as a fuel source if glucose levels are too low in the body.

Ketones serve as fuel in times of prolonged starvation or when patients suffer from uncontrolled diabetes and cannot utilize most of the circulating glucose.

Lipid metabolism - Wikipedia

In both cases, fat stores are liberated to generate energy through the Krebs cycle and will generate ketone bodies when too much acetyl CoA accumulates. Figure 4. Excess acetyl CoA is diverted from the Krebs cycle to the ketogenesis pathway. This reaction occurs in the mitochondria of liver cells. Organs that have classically been thought to be dependent solely on glucose, such as the brain, can actually use ketones as an alternative energy source. This keeps the brain functioning when glucose is limited. When ketones are produced faster than they can be used, they can be broken down into CO 2 and acetone.

The acetone is removed by exhalation.

This effect provides one way of telling if a diabetic is properly controlling the disease. The carbon dioxide produced can acidify the blood, leading to diabetic ketoacidosis, a dangerous condition in diabetics. Ketones oxidize to produce energy for the brain. The carbon within the acetoacetyl CoA that is not bonded to the CoA then detaches, splitting the molecule in two.

These two acetyl CoA molecules are then processed through the Krebs cycle to generate energy. Figure 5.

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  • When glucose is limited, ketone bodies can be oxidized to produce acetyl CoA to be used in the Krebs cycle to generate energy. When glucose levels are plentiful, the excess acetyl CoA generated by glycolysis can be converted into fatty acids, triglycerides, cholesterol, steroids, and bile salts. Lipoproteins containing more TG are with low density, and those containing less TG have higher density.

    According to the density of lipoproteins, plasma lipoproteins can be divided into four categories: 1 chylomicrons CM ; 2 very low density lipoprotein VLDL ; 3 low density lipoprotein LDL ; 4 high density lipoprotein HDL. After binding to lipids, proteins take part in transporting lipids in plasma, so they are called apolipoproteins.

    The mainly lipid source of the liver is food. In the small intestine, bile acids and pancreatic enzymes including pancreatic lipase, phospholipase A2, cholesterol esterase, etc. Then these molecules are absorbed by mucosal epithelial cells of the small intestine mainly jejunum , and are further esterified into TG, CE, etc.

    Finally, TG, Ch and PL with apolipoprotein compose of lipoprotein chylomicron CM which will be absorbed by the lymphatic system and hydrolyzed by lipoproteinase of vascular endothelial cells to enter the liver. The mainly source of endogenous fatty acids is the fat stored in the body's adipose tissue. The fat in the fat cells is hydrolyzed into glycerol and fatty acids by the action of lipase.

    After being released into the blood, glycerol is dissolved in plasma while fatty acids are combined with plasma albumin for transport. It can be used as a source of energy or ingested by liver cells again. In addition, hepatocytes also can produce fatty acids from the oxidation process of glucose and amino acids and synthesize TG by acetyl-CoA in hepatocytes.

    This is a major evolutionary insight that had eluded scientists for decades.

    Research Area

    Kenneth Verstraete explains: "Our 'tour-de-force' structural exploration of the mechanism and evolution of ACLY as a central metabolic enzyme is poised to reshape our understanding of biochemistry and will facilitate efforts to target human ACLY in widespread metabolic diseases and cancer. The central role of ACLY in human metabolism inspired its possible therapeutic relevance.

    Lipid Metabolism erininitor.tk4

    For instance, to support tumor growth many cancer cells show an increase in fatty acid production which depends on ACLY. In fact, in breast and lung cancer, one observes an increased activity of ACLY.

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    Furthermore, ACLY in the liver is a therapeutic target in metabolic disorders marked by high levels of blood triglycerides and cholesterol. Currently, the most advanced ACLY-targeting medicinal substance is bempedoic acid, which is under clinical evaluation as a promising treatment to lower low-density lipoprotein cholesterol LDL cholesterol, the 'unhealthy' type associated with atherosclerosis. Verstraete and his colleagues anticipate that the detailed structural and functional insights they have contributed will facilitate therapeutic targeting of human ACLY in metabolic diseases and cancer.

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    Lipid Metabolism

    Science News. Structure of ATP citrate lyase and the origin of citrate synthase in the Krebs cycle. Nature , DOI: ScienceDaily, 3 April Structure of the molecular machine that links carbohydrate and lipid metabolism.